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In this study, SantaCruz and colleagues have created an inducible mutant tau transgenic model, and observed the neuropathological consequences of strategically turning on and off tau expression for set periods. Profound forebrain neurodegeneration and memory loss by tau overexpression was observed. Remarkably, following termination of tau expression, tau hyperphosphorylation and tangle formation progressed while memory function recovered. These findings provide compelling evidence that neurofibrillary tangles do not directly serve a role in neuronal loss or cognitive impairment. This is consistent with a recent report by Peter Davies and colleagues that neurofibrillary pathology was not correlated with neuronal death in a human tau transgenic model displaying neurodegeneration (Andorfer et al., 2005). The study by SantaCruz et al. also provides the exciting prospective that recovery of cognitive function is possible even after significant progression of neurodegeneration. These findings have profound implications in the understanding of AD and other neurodegenerative disorders featuring tauopathy.

SantaCruz and colleagues manipulated transgenic tau levels using the tet-off system. Their results indicate that NFT accumulation is not sufficient to cause neuronal death and cognitive decline. This result was a bit of a surprise, because NFT formation increased even after transgenic tau expression was suppressed. Memory function also improved as suppressing tau expression halted brain atrophy. These results suggest that NFT formation, neuronal death, and cognitive decline may occur through different mechanisms in tauopathies. Moreover, it suggests that developing a tau aggregation inhibitor might not produce therapeutic benefits in such diseases. However, these results might very well be due to the effects of tau overexpression. Mandelkow’s group clearly showed that tau overexpression impaired anterograde axonal trafficking, which may cause synaptic dysfunction, eventually inducing memory failure and neuron death. When suppressing tau expression, axonal transport recovered. Memory function, therefore, might improve with the return of synaptic function.

Once the tau concentration increases, conformational changes, which account for the earliest aberrations in tau in AD (Weaver et al., 2000), occur that produce tau by-products that are resistant to degradation. These residual products form tau fibrils, NFTs, thereby explaining why NFTs increase even after tau expression is suppressed, and they may generate tau oligomers that cannot be removed. Tau fibrils would then remain even after suppressing tau overexpression. In the authors’ mouse model, the effect of tau overexpression is commonly used to express phenotype; yet, patients with the P301L mutation do not have overexpressed mutant tau. Rather, mRNA levels of mutant tau are the same as wild tau levels, and soluble mutant tau levels are smaller than those for wild tau (Miyasaka et al., 2001). This mutant tau expression, albeit small, induces tauopathy. Thus, it is not overexpression, but tau mutations that provoke tauopathy (that is, NFT formation, neuronal loss, and dementia). Therefore, investigating the effects of tau mutation might provide insights into what is happening in patients with FTDP-17.

Neurofibrillary Tangles: Villain or Merely Vilified? What’s Next? TADDLs/TAuDDLs!
For most investigators in the field of Alzheimer disease (AD), pathology has become equated with pathogenesis. As such, the two leading theories concerning the disease revolve around the amyloid-β of senile plaques and the phospho-tau of neurofibrillary tangles (NFTs). Contrasting this viewpoint, there a growing contingency suggesting that pathology is not central to pathogenesis; rather, pathology may even be the anti-pathogenesis and, rather than causing the disease, the pathology may be protecting from the disease (Rottkamp et al., 2002; Smith et al., 2002; Lee et al., 2005). A recent transgenic mouse study from Karen Ashe and colleagues (Santacruz et al., 2005) goes a long way toward bringing light to this specific issue. These studies quite convincingly demonstrate that NFT-like accumulations of phospho-tau are not associated with neurodegeneration, echoing a recent similar conclusion from the Peter Davies group (Andorfer et al., 2005). While these studies implicate NFTs as beneficial, since they are disconnected with cell death, better evidence for the exoneration of phospho-tau/NFTs in the disease process is provided by human studies (reviewed in Lee et al., 2005). For example, in patients with AD, phospho-tau and NFTs are unlikely to be factors in the neurodegenerative process since, while both the total number and length of microtubules are significantly and selectively reduced in pyramidal neurons, such decrements are unrelated to NFTs (Cash et al., 2003). This poses the question as to what causes the neurodegeneration. One suggestion is that NFTs sequester “abnormal” phospho-tau microaggregates, thereby rendering them harmless (Binder et al., 2005). Therefore, much like micro-aggregates of amyloid-β (ADDLs; Klein, 2002), the tau story has shifted to micro-aggregates of phospho-tau…let’s call them TADDLs or TAuDDLs (Tau-Derived Diffusible Ligands). The evidence for such TADDLs, much like their counterpart ADDLs (Lee et al., 2004), is scant but at least it keeps the prime suspects front and center. However, as we recently reviewed (Lee et al., 2005), there is far, far more evidence that phospho-tau, as TADDLs or NFTs, are a protective compensatory response mounted by neurons in an effort to stave off another driving pathogenic force. Indeed, oxidative damage not only chronologically precedes phospho-tau (Nunomura et al., 2000; Liu et al., 2005), but, supporting a protective response, such oxidative stress is significantly reduced in AD in neurons containing phospho-tau (Nunomura et al., 2001). Perhaps the time has come to reassess our old prejudices and exonerate the “villain.”

I found this paper fascinating and very intriguing, but could not determine whether the effects attributed to lowered tau levels (from the otherwise very high levels) are instead due to a neuroprotective effect of the drug used to control tau expression.